A major objective of the present application is to improve the state of the art of biomimetic polyene cyclization so that it may be employed for the synthesis of substances of biological and medicinal importance, particularly steroids and analogs, thus making them more readily accessible. It is planned to exploit a basically new approach for the enhancement and control of these cyclizations by the agency of cation-stabilizing ("C-S") functions located at sites in the substrate that are destined to develop positive character in the transition state. Exploitation of this methodology includes the specific aims of application to the asymmetric synthesis of members of the following types of products of known or potential medicinal value: mineralotropic and antiinflammatory corticoids (for treatment of various diseases, e.g., arthritis) and 19-norsteroidal compounds (for oral_contraception). In addition plans are presented for the synthesis of lazaroid (U-74006F (for treatment of CNS trauma and ischemia). In the course of these synthetic studies, the opportunity will become available for preparing a number of 8-fluoro steroid analogs. This unknown class of compounds may have important biological properties and arrangements for screening tests have been made with the Upjohn Company through Douglas R. Morton, Jr. Seminal positive results on the use of C-S auxiliaries have led to the suggestion of a mechanism for the enzymatic cyclization of oxidosqualene based on control by negative point charges provided by the enzyme. This mechanism has, in turn, led to the rational design of new structures for possible transition state analog inhibitors, some of which have the potential of being useful in moderating the biosynthesis of cholesterol in mammals (antihypocholesteremic effect) and of ergosterol in fungi. Syntheses of these structures have been commenced and tests for inhibition of OS cyclases will be conducted by P. Benveniste (University of Strasbourg). Arrangements for antifungal tests are being made with W. Kolimeyer at DuPont's Agricultural Products Department. If these compounds prove to be good inhibitors, they also should be useful in developing substances that will serve as haptens for eliciting monoclonal antibodies which may serve as catalysts for polyene cyclizations (see below). The antibody study is to be conducted in collaboration with J. H. Griffin (Stanford) who will perform the biological experiments. Long range objectives include, in addition to determining the mechanism of oxidosqualene cyclases, the development of catalysts for the asymmetric high-yield cyclization of synthetic substrates leading to steroidal products of medicinal importance.